Production of pyridoxine



United States Patent PRODUCTION OF PYRIDOXINE John Halley Mowat, Pearl River, N.Y., and John Schurr Webb, Woodciilf Lake, N.J., -assignors to American .Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Application October 31, 1957 Serial No. 693,527

3 Claims. (Cl. 260-2975) This invention relates to the production of pyridoxine, known also as vitamin B and as 2-methyl-3 hydroxy- 4,5-bis(hydroxymethyD-pyridine. More particularly, it relates to an improved process for the reduction to pyridoxine of a particular lactone-type pyridoxine intermediate and acyl derivatives thereof.

Among the many valuable intermediates useful in the synthesis of pyridoxine is the gamma lactone of '2-methyl- 3-hydroxy-4-carboxy-S-hydroxy-methyl pyridine which is described and claimed in US. Patent 2,457,484, issued to J. H. Mowat on December 28, 1948, wherein itis disclosed that the aforesaid lactone, hereinafter referred to as B lactone, has the formula and that it may be converted to pyridoxine by reduction in the presence of granulated tin and 30% hydrochloric acid. While the above-mentioned tin-hydrochloric acid reduction process is feasible technically, the yield of pyridoxine achieved thereby is not great enough to render the reaction a commercially attractive one.

We have now discovered, surprisingly, that if a lactonetype pyridoxine intermediate selected from the group consisting of the above'mentioned B lactone and acyl derivatives thereof, said group being characterized by the formula Where R is selected from the group consisting of hydrogen and acyl radicals, is reduced by means of reaction with a complex metal hydride of the group consisting of alkali metal aluminumhydrides and lithium borohydride the yield of pyridoxine obtained thereby is commercially attractive by virtue of being about forty times greater than that obtained by the above-mentioned tinhydrochloric acid process.

Reduction of organic compounds through the use of complex metal hydrides is presently considered a classic organicytype reaction and represents a well-developed art. In the literature there are clearteachings asto types of organic compounds that heretofore have been successfully reduced by the aforesaid classical reaction. Likewise there are clear teachings as to successful attempts heretofore made toward similar reduction of certain other types of organic compounds. Mariella and Belcher reported (Journal of the American Chemical ice Society 74, 4049 (1952)), that certain heterocyclic lactones were not successfully reduced to their corresponding 4,5bis(hydroxymethyl) derivatives by means of an alkali metal aluminum hydride. Among the aforesaid lactones is the lactone of 6-methyl-4-hydroxymethyl- 3-carboxy-pyridinone-2(1), designated lactone X, of the formula and obviously closely related structurally to B lactone, particularly because of the fact that in one of its possible tautomeric forms lactone Xa (shown above) it is simply a position isomer of B lactone. In view of such adverse teachings with respect to lactone X it was unexpected that compounds of the aforesaid group consisting of B lactone and acyl derivatives thereof proved to be reducible through reaction with a complex metal hydride of the group consisting of alkali metal aluminum hydrides and lithium borohydrides.

The conditions under which reduction of the above mentioned lactone-type pyridoxine type intermediates may be carried out by the process of our invention are essentially as follows: As the reaction medium, an inert ethereal organic solvent may be used. By the term inert ethereal organic solvent in this instance, we have in mind a solvent that is not unduly reactive towards the reactants, and contains one or more ether linkages,

' i.e., -CO-C, e.g., ethyl ether, dioxane, dibutyl ether, tetrahydrofuran, N-ethylmorpholine and the like, which are well known to be generally suitable for use in the complex metal hydride reduction reaction. The reaction temperature may vary between about 0 C. and C. ,The molar ratio of alkali metal aluminum hydride to the lactone type pyridoxine intermediate may vary between about 1:1 and about 6:1 .for optimum results, although slightly higher ratios may be used effectively if so desired. The reaction time, varying inversely withthe reaction temperature, may be about an hour or so at elevated temperatures and several days at lower temperatures.

In carrying out the above-described reaction the complex metal hydride is at the outset dissolved in the above-mentioned inert ethereal organic solvent. Subsequently the hydride solution and the lactone-type pyridoxine intermediate, in dry form or dissolved or suspended in a suitable quantity of the inert ethereal solvent, are mixed by conventional means to initiate the reaction. Because of the exothermic nature of the reduction reaction it is usually preferable to add the B lactone to the hydride solution.

Pyridoxine, which is the end product of the abovedescribed reaction, is recovered therefrom by conventional means as follows: The reaction is terminated by cooling the final mixture to room temperature or below, if .it is not already within that temperature range, followed by cautious additions of Water and strong aqueous alkali solution, e.g., 15% aqueous sodium hydroxide solution, respectively, to the cool reaction mixture. Following this, the resulting inorganic sludge is filtered off and the resulting filtrate which contains the pyridoxine is evaporated under vacuum leaving either a dry or an oily residue which is then dissolved in a lower alkyl alcohol such as ethanol. At this stage the resulting alcohol solution is saturated with HCl gas to convert the pyridoxine to pyridoxine hydrochloride. Pyridoxine the result that the 3-position will, at the end of our herein described reaction, be occupied by a hydroxyl group. Any such extensive list of acylradicals would include such alkanoyl radicals as acetyl, propionyl, butyryl, lauroyl, etc., and such aroyl radicals as benzoyl, etc., to name some of the Well-known acyl radicals. The acyl groups suitable for our invention will be readily discernible by those skilled in the art.

The following examples will serve to illustrate our invention:

Example 1 One gram (0.025 mole) of lithium aluminum hydride was stirred into 150 ml. of tetrahydrofuran until solution was complete. One gram (0.006 mole) of the lactone of 2-methyl-3-hydroxy-4-carboxy-5-hydroxymethyl pyridine in hot tetrahydrofuran solution was added slowly. The reaction was allowed to proceed at reflux temperature for a period of two hours, cooled in an ice bath, and carefully decomposed by the addition of 1 ml. of water, 3 ml. of sodium hydroxide solution and 3 ml. of water in that order. Then 2.3 ml. of concentrated hydrochloric acid was added to the mixture followed by 100 ml. of water. The inorganic sludge was removed by filtration. The filtrate was concentrated under vacuo to a residue and extracted with 200 ml. of ethanol. The alcohol extract was concentrated under vacuo to a 50 ml. volume and treated with hydrogen chloride gas at 2530 C. The product was removed by filtration, washed with 5 ml. of cold ethanol, and dried at 50 C. The yield of product was 0.49 g. The final product had a melting point of 210-212 C. and an infrared absorption spectrum identical with authentic U.S.P. pyridoxine hydrochloride.

Example 2 1.46 gram (0.026 mole) of sodium aluminum hydride was stirred into 200 ml. of tetrahydrofuran. One part (0.006 mole) of the lactone of 2-methyl-3-hydroxy-4- carboxy-S-hydroxymethyl pyridine was added to the solution and the mixture heated to reflux and maintained at reflux for a period of four hours. The reaction mixture was cooled and cautiously decomposed with additions of 1.5 ml. of water, 2 ml. of 15 sodium hydroxide solution and 125 ml. of water, added in that order. The inorganic sludge was removed by filtration with the aid of aluminum silicate. The filtrate was saturated with carbon dioxide and allowed to stand for 24 hours at room temperature. A small amount of insoluble material was removed by filtration and the filtrate concentrated by distillation under vacuo. The residue, extracted with 200 ml. of ethanol, was saturated with hydrogen chloride gas at room temperature and evaporated under vacuo until incipient crystallization. Upon further cooling addi tional crystallization occurred, the product removed by filtration, washed with 5 ml. of cold ethanol, and air dried at 50 C. The infrared spectra data for the product were identical with those for U.S.P. authentic pyridoxine hydrochloride.

4 Example 3 Heated together at 90 C. under reflux for about an hour were the lactone of 2-methyl-3-hydroxy-4-carboxy- S-hydroxymethyl pyridine (16 grams) and acetic anhydride (130 grams). The resulting clear solution was treated with decolorizing carbon, filtered, and cooled. The crystals which separated out were then isolated by filtration and dried under vacuum to give 14 grams of lactone of 2-methyl-3 acetoxy 4 carboxy 5 hydroxymethyl pyridine. The melting point of the product was 165-167 C.

Example 4 One gram (0.025 mole) of lithium aluminum hydride was added to 150 ml. of diethyl ether and the slurry stirred for a period of about two hours to effect dissolution. Then 0.8 gram (0.038 mole) of the lactone of 2-methyl-3-acetoxy-4-carboxy-5-hydroxymethyl pyridine, as prepared in Example 3, was added as a solution in cool diethyl ether to the hydride solution, whereupon the resulting solution was heated to reflux and held at reflux for three hours. The reaction mixture was cooled with the aid of an ice bath and decomposed carefully with 10 ml. of water at 1516 C. An additional 90 ml. of water was added to the mixture and it was filtered with the aid of 2 grams of aluminum silicate. The diethyl ether was removed by evaporation and filtrate saturated with carbon dioxide. The water was removed by distillation under vacuum and the residue extracted with 200 ml. of ethanol. The ethanol extract was saturated with hydrogen chloride gas, concentrated under vacuum until incipient crystallization and allowed to cool. The product was removed by filtration, washed with 10 ml. of cold ethyl alcohol, and then air dried at 50 C. The yield of product was 0.465 g. The product had a melting point of 210-2l2 C. and an infrared spectrum identical with that for authentic U.S.P. pyridoxine hydrochloride.

We claim:

1. A process of preparing pyridoxine which comprises reacting in an inert ethereal organic solvent at lactone of the formula 0 o-o no I (L11, on

where R is a member of the group consisting of hydrogen and an acyl radical with a complex metal hydride of the group consisting of an alkali metal aluminum hydride and lithium borohydride until a substantial quantity of t pyridoxine is formed.

2. The process of claim 1 where the complex metal hydride is lithium aluminum hydride.

3. The process of claim 1 where the complex metal hydride is sodium aluminum hydride.

References Cited in the file of this patent UNITED STATES PATENTS 2,037,876 Bousquet Apr. 21, 1936 2,248,078 Harris July 8, 1941 2,650,232 Jones Aug. 25, 1953 2,744,114 Jones May 1, 1956 OTHER REFERENCES Krajkeman: Manufacturing Chemist XXII, 4, April 1951, pp. 147-156.

UNITED STATES PATENT oTTmE CERTIFICATE 01F (@ECTION Patent No, 2 918 471 December 22 1959 John Halley Mowat et al0 It is herebj certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l line 619 for "successful" read unsuccessful. column 3 line .2 for to read of Signed and sealed this 6th day of September 1960(,

(SEAL) Attest:

ERNEST We SWIDER ROBERT C. WATSON Attesting Officer Commissioner of Patents 

1. A PROCESS OF PREPARING PYRIDOXINE WHICH COMPRISES REACTING IN AN INERT ETHEREAL ORGANIC SOLVENT A LACTONE OF THE FORMULA 